{"id":4277,"date":"2025-09-26T12:32:07","date_gmt":"2025-09-26T05:32:07","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=4277"},"modified":"2025-11-15T13:52:28","modified_gmt":"2025-11-15T06:52:28","slug":"bupivacaine-hydrochloride","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/bupivacaine-hydrochloride\/","title":{"rendered":"Bupivacaine Hydrochloride"},"content":{"rendered":"

(Ph. Eur. monograph 0541)<\/p>\n

C_{18<\/sub>H_{29<\/sub>ClN_{2<\/sub>O,H_{2<\/sub>O\u00a0 \u00a0 \u00a0342.9\u00a0 \u00a0 \u00a073360-54-0<\/p>\n}}}}

Action and use<\/strong><\/p>\n

Local anaesthetic.<\/p>\n

Preparations<\/strong><\/p>\n

Bupivacaine Injection<\/p>\n

Bupivacaine Heavy Injection<\/p>\n

Bupivacaine and Adrenaline Injection\/Bupivacaine and Epinephrine Injection<\/p>\n

Bupivacaine and Diamorphine Injection<\/p>\n

Bupivacaine and Fentanyl Injection<\/p>\n

DEFINITION<\/h2>\n
(2RS)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide hydrochloride monohydrate.<\/p>\n
Content<\/h3>\n
98.5 per cent to 101.0 per cent (dried substance).<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
White or almost white, crystalline powder or colourless crystals.<\/p>\n
Solubility<\/h3>\n
Soluble in water, freely soluble in ethanol (96 per cent).<\/p>\n
IDENTIFICATION<\/h2>\n
First identification: A, C, D.<\/p>\n
Second identification: B, C.<\/p>\n
A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: bupivacaine hydrochloride CRS.<\/p>\n
B. Thin-layer chromatography (2.2.27).<\/p>\n
Test solution: Dissolve 25 mg of the substance to be examined in methanol R and dilute to 5 mL with the same solvent.<\/p>\n
Reference solution: Dissolve 25 mg of bupivacaine hydrochloride CRS in methanol R and dilute to 5 mL with the same solvent.<\/p>\n
Plate: TLC silica gel G plate R.<\/p>\n
Mobile phase: concentrated ammonia R, methanol R (0.1:100 V\/V).<\/p>\n
Application: 5 \u03bcL.<\/p>\n
Development: Over a path of 10 cm.<\/p>\n
Drying: In air.<\/p>\n
Detection: Spray with dilute potassium iodobismuthate solution R.<\/p>\n
Results: The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.<\/p>\n
C. It gives reaction (a) of chlorides (2.3.1).<\/p>\n
D. Optical rotation (see Tests).<\/p>\n
TESTS<\/h2>\n
Solution S<\/h3>\n
Dissolve 1.0 g in carbon dioxide-free water R and dilute to 50 mL with the same solvent.<\/p>\n
Appearance of solution<\/h3>\n
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n
Acidity or alkalinity<\/h3>\n
To 10 mL of solution S add 0.2 mL of 0.01 M sodium hydroxide; the pH (2.2.3) is not less than 4.7. Add 0.4 mL of 0.01 M hydrochloric acid; the pH is not greater than 4.7.<\/p>\n
Optical rotation (2.2.7)<\/h4>\n
-0.10\u00b0 to + 0.10\u00b0.<\/p>\n
Dissolve 1.0 g in methanol R and dilute to 20.0 mL with the same solvent.<\/p>\n
Related substances<\/h3>\n
Gas chromatography (2.2.28).<\/p>\n
Internal standard solution: Dissolve 25 mg of methyl behenate R in methylene chloride R and dilute to 500 mL with the same solvent.<\/p>\n
Test solution: Dissolve 50.0 mg of the substance to be examined in 2.5 mL of water R, add 2.5 mL of dilute sodium hydroxide solution R and extract with 2 quantities, each of 5 mL, of the internal standard solution. Filter the lower layer.<\/p>\n
Reference solution (a): Dissolve 10 mg of the substance to be examined, 10 mg of bupivacaine impurity B CRS and 10 mg of bupivacaine impurity E CRS in 2.5 mL of water R, add 2.5 mL of dilute sodium hydroxide solution R and extract with 2 quantities, each of 5 mL, of the internal standard solution. Filter the lower layer and dilute to 20 mL with the internal standard solution.<\/p>\n
Reference solution (b): Dilute 1.0 mL of the test solution to 100.0 mL with the internal standard solution.<\/p>\n
Reference solution (c): Dilute 5.0 mL of reference solution (b) to 10.0 mL with the internal standard solution.<\/p>\n
Reference solution (d): Dilute 1.0 mL of reference solution (b) to 10.0 mL with the internal standard solution.<\/p>\n
Column:<\/p>\n
\u2014 material: fused silica;<\/p>\n
\u2014 size: l = 30 m, \u00d8 = 0.32 mm;<\/p>\n
\u2014 stationary phase: phenyl(5)methyl(95)polysiloxane R (film thickness 0.25 \u03bcm).<\/p>\n
Carrier gas: helium for chromatography R.<\/p>\n
Flow rate: 2.5 mL\/min.<\/p>\n
Split ratio: 1:12.<\/p>\n
Temperature:<\/p>\n\n\n\n\n\n\n\n\n
<\/td>\n Time<\/strong>
\n(min)<\/strong><\/td>\n Temperature<\/strong>
\n(\u00b0C)<\/strong><\/td>\n<\/tr>\n
<\/td>\n 0<\/td>\n 180<\/td>\n<\/tr>\n
Column<\/td>\n 0 – 10<\/td>\n 180 \u2192 230<\/td>\n<\/tr>\n
<\/td>\n 10 – 15<\/td>\n 230<\/td>\n<\/tr>\n
Injection port<\/td>\n <\/td>\n 250<\/td>\n<\/tr>\n
Detector<\/td>\n <\/td>\n 250<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Detection: Flame ionisation.<\/p>\n
Injection: 1 \u03bcL.<\/p>\n
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peaks due to impurities B and E.<\/p>\n
Relative retention: With reference to bupivacaine (retention time = about 10 min): impurity B = about 0.7; impurity E = about 1.1; internal standard = about 1.4.<\/p>\n
System suitability: Reference solution (a):<\/p>\n
\u2014 resolution: minimum 3.0 between the peaks due to bupivacaine and impurity E.<\/p>\n
Limits:<\/p>\n
\u2014 impurity B: calculate the ratio (R_{1<\/sub>) of the area of the principal peak to the area of the peak due to the internal standard from the chromatogram obtained with reference solution (c); from the chromatogram obtained with the test solution, calculate the ratio of the area of the peak due to impurity B to the area of the peak due to the internal standard: this ratio is not greater than R_{1 <\/sub>(0.5 per cent);<\/p>\n}}
\u2014 unspecified impurities: calculate the ratio (R_{2<\/sub>) of the area of the principal peak to the area of the peak due to the internal standard from the chromatogram obtained with reference solution (d); from the chromatogram obtained with the test solution, calculate for each impurity the ratio of the area of any peak, apart from the principal peak, the peak due to impurity B and the peak due to the internal standard, to the area of the peak due to the internal standard: this ratio is not greater than R_{2<\/sub> (0.10 per cent);<\/p>\n}}
\u2014 total: calculate the ratio (R_{3<\/sub>) of the area of the principal peak to the area of the peak due to the internal standard from the chromatogram obtained with reference solution (b); from the chromatogram obtained with the test solution, calculate the ratio of the sum of the areas of any peaks, apart from the principal peak and the peak due to the internal standard, to the area of the peak due to the internal standard: this ratio is not greater than R_{3 <\/sub>(1.0 per cent);<\/p>\n}}
\u2014 disregard limit: ratio less than 0.05 times R_{3<\/sub> (0.05 per cent).<\/p>\n}
Impurity F<\/h3>\n
Liquid chromatography (2.2.29). Prepare the solutions immediately before use.<\/p>\n
Test solution: Dissolve 50 mg of the substance to be examined in mobile phase A and dilute to 10.0 mL with mobile phase A.<\/p>\n
Reference solution (a): Dissolve 5.0 mg of bupivacaine impurity F CRS in mobile phase A and dilute to 100.0 mL with mobile phase A. Dilute 1.0 mL of the solution to 100.0 mL with mobile phase A. Dilute 1.0 mL of this solution to 10.0 mL with mobile phase A.<\/p>\n
Reference solution (b): Dissolve 20 mg of methyl benzoate R and 25 mg of bupivacaine impurity F CRS in mobile phase A and dilute to 50 mL with mobile phase A. Dilute 3 mL of the solution to 50 mL with mobile phase A. Dilute 1 mL of this solution to 10 mL with mobile phase A.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n
\u2014 stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 \u03bcm).<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: dissolve 0.23 g of sodium dihydrogen phosphate monohydrate R and 3.626 g of disodium hydrogen phosphate dihydrate R in water for chromatography R and dilute to 1000 mL with the same solvent; mix equal volumes of this solution (pH 8.0) and acetonitrile for chromatography R;<\/p>\n
\u2014 mobile phase B: acetonitrile for chromatography R;<\/p>\n\n\n\n\n\n\n
Time<\/strong>
\n(min)<\/strong><\/td>\n Mobile phase A<\/strong>
\n(per cent V\/V)<\/strong><\/td>\n Mobile phase B<\/strong>
\n(per cent V\/V)<\/strong><\/td>\n<\/tr>\n
0 – 10<\/td>\n 100<\/td>\n 0<\/td>\n<\/tr>\n
10 – 15<\/td>\n 100 \u2192 80<\/td>\n 0 \u2192 20<\/td>\n<\/tr>\n
15 – 25<\/td>\n 80<\/td>\n 20<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Flow rate: 1.0 mL\/min.<\/p>\n
Detection: Spectrophotometer at 240 nm.<\/p>\n
Injection: 50 \u03bcL.<\/p>\n
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peak due to impurity F.<\/p>\n
Relative retention: With reference to bupivacaine (retention time = about 20 min): impurity F = about 0.3; methyl benzoate = about 0.4.<\/p>\n
System suitability:<\/p>\n
\u2014 resolution: minimum 4.0 between the peaks due to impurity F and methyl benzoate in the chromatogram obtained with reference solution (b);<\/p>\n
\u2014 signal-to-noise ratio: minimum 40 for the principal peak in the chromatogram obtained with reference solution (a).<\/p>\n
Limit:<\/p>\n
\u2014 impurity F: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (10 ppm).<\/p>\n
Loss on drying (2.2.32)<\/h4>\n
4.5 per cent to 6.0 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C.<\/p>\n
Sulfated ash (2.4.14)<\/h4>\n
Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n
ASSAY<\/h2>\n
Dissolve 0.250 g in a mixture of 20 mL of water R and 25 mL of ethanol (96 per cent) R. Add 5.0 mL of 0.01 M hydrochloric acid. Carry out a potentiometric titration (2.2.20), using 0.1 M ethanolic sodium hydroxide. Read the volume added between the 2 points of inflexion.<\/p>\n
1 mL of 0.1 M ethanolic sodium hydroxide is equivalent to 32.49 mg of C_{18<\/sub>H_{29<\/sub>ClN_{2<\/sub>O.<\/p>\n}}}
STORAGE<\/h2>\n
Protected from light.<\/p>\n
IMPURITIES<\/h2>\n
Specified impurities B, F.<\/p>\n
Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other\/unspecified impurities and\/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) A, C, D, E.<\/p>\n
$\"Bupivacaine$ <\/p>\n
A. N-(2,6-dimethylphenyl)pyridine-2-carboxamide,<\/p>\n
$\"Bupivacaine$ <\/p>\n
B. (2RS)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide,<\/p>\n
$\"Bupivacaine$ <\/p>\n
C. 1-(2,6-dimethylphenyl)-1,5,6,7-tetrahydro-2H-azepin-2-one,<\/p>\n
$\"Bupivacaine$ <\/p>\n
D. (2RS)-2,6-dichloro-N-(2,6-dimethylphenyl)hexanamide,<\/p>\n
$\"Bupivacaine$ <\/p>\n
E. 6-(butylamino)-N-(2,6-dimethylphenyl)hexanamide,<\/p>\n
$\"Bupivacaine$ <\/p>\n
F. 2,6-dimethylaniline.<\/p>\n","protected":false},"excerpt":{"rendered":"
(Ph. Eur. monograph 0541) C18H29ClN2O,H2O\u00a0 \u00a0 \u00a0342.9\u00a0 \u00a0 \u00a073360-54-0 Action and use Local anaesthetic. Preparations Bupivacaine Injection Bupivacaine Heavy Injection Bupivacaine and Adrenaline Injection\/Bupivacaine and Epinephrine Injection Bupivacaine and Diamorphine Injection Bupivacaine and Fentanyl Injection DEFINITION (2RS)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide hydrochloride monohydrate. Content 98.5 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance White or almost white,…<\/p>\n","protected":false},"author":2,"featured_media":4282,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-4277","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicinal-substances"],"acf":[],"_links":{"self":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/4277","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=4277"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/4277\/revisions"}],"predecessor-version":[{"id":5253,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/4277\/revisions\/5253"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/4282"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=4277"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=4277"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=4277"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

Content<\/h3>\n98.5 per cent to 101.0 per cent (dried substance).<\/p>\n

CHARACTERS<\/h2>\n

Appearance<\/h3>\nWhite or almost white, crystalline powder or colourless crystals.<\/p>\n

Solubility<\/h3>\nSoluble in water, freely soluble in ethanol (96 per cent).<\/p>\n

TESTS<\/h2>\n

Solution S<\/h3>\nDissolve 1.0 g in carbon dioxide-free water R and dilute to 50 mL with the same solvent.<\/p>\n

Appearance of solution<\/h3>\nSolution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n

Acidity or alkalinity<\/h3>\nTo 10 mL of solution S add 0.2 mL of 0.01 M sodium hydroxide; the pH (2.2.3) is not less than 4.7. Add 0.4 mL of 0.01 M hydrochloric acid; the pH is not greater than 4.7.<\/p>\n

Optical rotation (2.2.7)<\/h4>\n-0.10\u00b0 to + 0.10\u00b0.<\/p>\nDissolve 1.0 g in methanol R and dilute to 20.0 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h4>\n4.5 per cent to 6.0 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C.<\/p>\n

Sulfated ash (2.4.14)<\/h4>\nMaximum 0.1 per cent, determined on 1.0 g.<\/p>\n

STORAGE<\/h2>\nProtected from light.<\/p>\n

Content<\/h3>\n
98.5 per cent to 101.0 per cent (dried substance).<\/p>\n

Appearance<\/h3>\n
White or almost white, crystalline powder or colourless crystals.<\/p>\n

Solubility<\/h3>\n
Soluble in water, freely soluble in ethanol (96 per cent).<\/p>\n

Solution S<\/h3>\n
Dissolve 1.0 g in carbon dioxide-free water R and dilute to 50 mL with the same solvent.<\/p>\n

Appearance of solution<\/h3>\n
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n

Acidity or alkalinity<\/h3>\n
To 10 mL of solution S add 0.2 mL of 0.01 M sodium hydroxide; the pH (2.2.3) is not less than 4.7. Add 0.4 mL of 0.01 M hydrochloric acid; the pH is not greater than 4.7.<\/p>\n

Optical rotation (2.2.7)<\/h4>\n
-0.10\u00b0 to + 0.10\u00b0.<\/p>\n
Dissolve 1.0 g in methanol R and dilute to 20.0 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h4>\n
4.5 per cent to 6.0 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C.<\/p>\n

Sulfated ash (2.4.14)<\/h4>\n
Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n

STORAGE<\/h2>\n
Protected from light.<\/p>\n